The cross talk of two family members of ß-TrCP in the regulation of cell autophagy and growth.

ABSTRACT

ß-transducin repeat-containing protein (ß-TrCP), one of the best-characterized substrate recognition components of the SKP1-CUL1-F-box (SCF) E3 ligase, has two distinct paralogs, ß-TrCP1 and ß-TrCP2, expressed in mammals. Through governing the ubiquitination and degradation of numerous key regulators, ß-TrCP1/2 regulates various cellular physiological and pathological processes. However, whether and how these two proteins cross talk and whether they regulate cell autophagy and proliferation in different manners is completely unknown. Herein, we report that ß-TrCP1 and ß-TrCP2 are the physiological substrates of SCF E3 ligase and target each other for degradation that is dependent on their ß-TrCP degron sequences. Furthermore, glucose deprivation activates AMPK kinase to phosphorylate ß-TrCP1 and promotes the subsequent ubiquitination and degradation of ß-TrCP1 by ß-TrCP2, but does not promote ß-TrCP2 degradation by ß-TrCP1. Finally, we found that ß-TrCP2, not ß-TrCP1, preferentially degrades DEPTOR and REDD1, the inhibitors of mTORC1, to activate mTORC1, leading to autophagy inhibition and cell growth. Thus, our study demonstrates that ß-TrCP1 and ß-TrCP2 mutually target each other for degradation and that ß-TrCP2 acts as a dominant paralog in the regulation of cell autophagy and growth, which might be a promising anticancer target.